Inhibition of LPS-Induced PGE2 Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme

Misong Kim,Kyung-Tae Lee,Yunchan Nam,Changyoung Jang,Jaeyeol Lee

doi:10.3390/proceedings2019022037

Abstract

Microsomal prostaglandin E synthase-1 (mPGES-1) is responsible for the massive prostaglandin E2 (PGE2) formation during inflammation. Increasing evidence reveals mPGES-1 inhibitors as a safe alternative to nonsteroidal anti-inflammatory drugs. Recently, we reported that a novel series of phenylsulfonyl hydrazide derivatives could reduce LPS-induced PGE2 levels in RAW 264.7 macrophage cells via an inhibition of the mPGES-1 enzyme. However, a few of the phenylsulfonyl hydrazide derivatives showed poor metabolic stability in liver microsomes. In order to identify new mPGES-1 inhibitors with improved metabolic stability, therefore, a series of arylsulfonamide derivatives has been synthesized and biologically evaluated against PGE2 production and the mPGES-1 enzyme. Among them, MPO-0186 inhibits the production of PGE2 (IC50 = 0.20 μM) in A549 cells via inhibition of mPGES-1 (IC50 = 0.49 μM in a cell-free assay) together with high selectivity over both COX-1 and COX-2. A molecular docking study theoretically suggests that MPO-0186 could inhibit PGE2 production by blocking the PGH2 binding site of the mPGES-1 enzyme. Furthermore, MPO-0186 demonstrated good metabolic stability in human liver microsomes and no significant inhibition observed in clinically relevant CYP isoforms.

Highlights

Inhibition of LPS-Induced prostaglandin E2 (PGE2) Production by Arylsulfonamide Derivatives via the Selective Inhibition of Microsomal prostaglandin E synthase-1 (mPGES-1) Enzyme †
2 Department of Life and Nanopharmaceutical Science, Kyung Hee University, Seoul 02447, Korea 3 KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Korea * Correspondence: miisong@khu.ac.kr † Presented at the 2nd Molecules Medicinal Chemistry Symposium (MMCS): Facing Novel Challenges in
We reported that a novel series of phenylsulfonyl hydrazide derivatives could reduce LPS-induced prostaglandin E2 (PGE2) levels in RAW 264.7 macrophage cells via an inhibition of the Microsomal prostaglandin E synthase-1 (mPGES-1) enzyme

Summary

Introduction

Inhibition of LPS-Induced PGE2 Production by Arylsulfonamide Derivatives via the Selective Inhibition of mPGES-1 Enzyme † Misong Kim 1,*, Changyoung Jang 1, Yunchan Nam 1, Kyung-Tae Lee 2 and Jaeyeol Lee 1,3 Research Institute for Basic Sciences and Department of Chemistry, College of Sciences, Kyung Hee University, Seoul 02447, Korea

Results

Conclusion